Cross-linked ultra-high molecular weight polyethylene for medical implant use

ABSTRACT

The present invention relates to the prevention and decrease of osteolysis produced by wear of the ultrahigh molecular weight polyethylene (UHMWPE). Methods are disclosed for the isolation of wear particles, preparation of implants exhibiting decreased wear in comparison to conventional UHMWPE and preparation of implants that cause decreased biological response in comparison to conventional UHMWPE. The implants created by these methods are also included in the present invention.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention generally relates to the field of orthopaedicimplants. Specifically the prevention and decrease of osteolysisproduced by wear of ultrahigh molecular weight polyethylene (UHMWPE)bearing components. Methods are disclosed for the isolation of wearparticles, preparation of implants having decreased wear and preparationof implants causing decreased biological response. The implants createdby these methods are also included in the present invention.

[0003] 2. Related Art

[0004] Ultrahigh molecular weight polyethylene (UHMWPE) is commonly usedas an articulating, load-bearing surface in total joint arthoplasty dueto its unique array of properties. UHMWPE offers toughness, low frictioncoefficient, and biocompatibility. (Baker et al., 1999) Total jointprosthesis, composed of various combinations of metal, ceramic, andpolymeric components, suffer from limited service lives and wear ofUHMWPE is the limiting factor. It has become apparent that wear debrisfrom UHMWPE components may be a primary contributor to osteolysis,loosening and eventual revision surgery. With steady increases in humanlife expectancy, there is a driving need to significantly increase theeffective lifetime of a single implant. A desire to use prostheticimplants in younger patients is another strong incentive for improvingthe wear resistance of UHMWPE. The present invention discloses a processto improve long term wear characteristics of prosthetic implants madewith UHMWPE.

[0005] When a human joint is destroyed or damaged by disease or injury,surgical replacement (arthoplasty) is normally required. A total jointreplacement includes components that simulate a natural human joint,typically:

[0006] (a) a more-or-less spherical ceramic or metal ball, often made ofcobalt chromium alloy;

[0007] (b) attachment of a “stem”, which is generally implanted into thecore of the adjacent long bone; and

[0008] (c) a hemispherical socket which takes the place of theacetabular cup and retains the spherical ball.

[0009] This hemispherical joint typically is a metal cup affixed intothe joint socket by mechanical attachments and is lined with UHMWPE. Inthis way, the ball can rotate, pivot, and articulate within the socket,and the stem, via the ball, can pivot and articulate.

[0010] One of the difficulties in constructing any device forimplantation into the human body is the need to avoid adverse hostbiological responses. The probability of adverse host reaction isreduced when certain synthetic materials are used. For example,synthetic UHMWPE implants have minimal immunogenicity and are not toxic.However, the wear and breakdown of the UHMWPE components are known inthe art to cause host cellular responses, which ultimately lead torevision surgery.

[0011] Histologic studies have demonstrated that wear of UHMWPE fromorthopaedic inserts leads to several reactions. First, the tissuesurrounding implants that were constructed with UHMWPE has been shown tocontain extremely small particles of UHMWPE that range from sub-micronto a few microns in size. While large particles of UHMWPE appear to betolerated by the body, as is the intact solid wall of the UHMWPEimplant, the body apparently does not tolerate smaller particles ofUHMWPE. In fact, the small particles of UHMWPE can cause histiocyticreactions by which the body attempts to eliminate the foreign material.Agents released during this process cause wear debris inducedosteolysis. This in turn can lead to loss of fixation and loosening ofthe prosthesis.

[0012] Numerous techniques have been proposed to improve wear resistanceof UHMWPE in orthopaedic implants. In these instances, however, many ofthe new versions of articulating polymers have generally failed todemonstrate significant reduction in wear and often prove to be inferiorto conventional polyethylene. Recent attempts at improving wearproperties of UHMWPE use special pressure/temperature processingtechniques, surface treatments, formation of composites with highmodulus fibers, and crosslinking via ionizing irradiation or chemicalagents. Some of these attempts are summarized below.

[0013] Temperature/Pressure Treatments

[0014] Special thermal and pressure treatments have been used toincrease physical performance and wear resistance of UHMWPE (e.g., U.S.Pat. Nos. 5,037,928 and 5,037,938). For example, “Hipping” (HotIsostatic Pressing), produces material alleged to comprise fewer fusiondefects, increased crystallinity, density, stiffness, hardness, yieldstrength and resistance to creep, oxidation, and fatigue. Clinicalstudies, however, indicate that “Hipping” treated UHMWPE may possessinferior wear resistance in comparison to conventional UHMWPE. Theinferior wear resistance being due to increased stiffness which leads toincreased contact stresses during articulation (Livingston et al.,Trans. ORS, 22, 141-24, 1997).

[0015] Post-consolidation temperature and pressure treatment, such assolid phase compression molding (Zachariades, U.S. Pat. No. 5,030,402),have also been attempted. Zachariades utilized solid state processing tofurther consolidate and orient UHMWPE chains. Resistance to wear inorthopaedic implants, however, was not improved.

[0016] Surface Treatments

[0017] Focusing upon the surface of UHMWPE components, attempts havebeen made to decrease wear by increasing smoothness and/or lubricity ofthe UHMWPE components surface. A group from Howmedica used a heatpressing technique to melt the articulating surface and remove machinemarks from the surface of UHMWPE components such that the “wearing in”of rough machine marks could be avoided. This modification, however,resulted in delamination and high wear due to the fact that higharticulation—induced stresses were located in regions where there was asharp transition in crystalline morphology (Bloebaum et al., Clin.Orthop. 269, 120-127, 1991).

[0018] Andrade et al. (U.S. Pat. No. 4,508,606) suggested oxidizing thesurface of a wet hydrophobic polymer surface to reduce sliding friction.The preferred means included applying a radio frequency glow dischargeto the surface. With this technique, surface chemistries were altered bychanging the time of gas plasma exposure and by altering the gascomposition. The invention was proposed for the treatment of cathetersto decrease surface friction properties while in a wet state. Similarly,Farrar (World Patent Application No. WO 95 212212) proposed using gasplasma treatments to crosslink the surface of UHMWPE and, thereby,increase its wear resistance. None of the plasma treatments, however,were practical because any perceived benefit would most likely wear awaywith articulation.

[0019] Composites

[0020] Because creep may be a contributor to UHMWPE wear, investigatorshave also included high modulus fibers in polyethylene matrices toreduce plastic deformation. (U.S. Pat. No. 4,055,862 discloses a“poly-to-carbon polyethylene composite” which failed significantly viadelamination. Recently, Howmedica reported that a PET/carbon fibercomposite exhibited 99% less hip simulated wear than conventionalpolyethylene over ten million cycles. (Polineni, V. K. et al., J.44^(th) Annual ORS, 49, 1998.)

[0021] Crosslinking

[0022] Radiation Induced Crosslinking

[0023] In the absence of oxygen, the predominant effect of ionizingradiation on UHMWPE is crosslinking (Rose et al., 1984, Streicher etal., 1988). Crosslinking of UHMWPE forms covalent bonds between polymerchains which inhibit cold flow (creep) of individual polymer chains.Free radicals formed during irradiation, however, can exist indefinitelyif termination by crosslinking or other forms of recombination do notoccur. Furthermore, reacted intermediates are continuously formed anddecayed. Exposure of these free radical species at any time (e.g.,during irradiation, shelf-aging, or in vivo aging) to molecular oxygenor any other reactive oxidizing agent can result in their oxidation.Extensive oxidation leads to a reduction in molecular weight, andsubsequent changes in physical properties, including wear resistance.

[0024] To reduce oxidation after gamma sterilization, some orthopaedicmanufacturers have implemented techniques to irradiate their materialsunder conditions that encourage crosslinking and reduce oxidation. Thesetechniques include use of inert gas atmospheres during all stages ofprocessing, use of vacuum packaging, and post sterilization thermaltreatments. Specific examples of these techniques are given below.

[0025] Howmedica has developed various means for reducing UHMWPEoxidation associated with processing, i.e., the continual use of aninert gas during processing (see U.S. Pat. Nos. 5,728,748; 5,650,485;5,543,471; 5,414,049; and 5,449,745). These patents also describethermal annealing of the polymer to reduce or eliminate free radicals.The annealing temperature which is claimed (room temperature to 135°C.), however, avoids complete melting of UHMWPE.

[0026] Johnson & Johnson has disclosed in a European patent application(EP 0737481 A1) a vacuum packaging method with subsequent irradiationsterilization to promote crosslinking and reduce short- and long-termoxidative degradation. The packaging environment can contain an inertgas and/or hydrogen to “quench” free radicals. Thecrosslinking/sterilization method is claimed to enhance UHMWPE wearresistance (Hamilton, J. V. et al., Scientific Exhibit, 64^(th) AAOSMeeting, February 1997; Hamilton, J. V. et al., Trans 43^(rd) ORS, 782,1997.).

[0027] Biomet's World Patent Application No. 97/29787 discloses thegamma irradiation of a prosthetic component in an oxygen resistantcontainer partially filled with a gas capable of combining with freeradicals (e.g., hydrogen).

[0028] Oonishi/Mizuho Medical Company-Japan and other investigators fromMizuho Medical Company began crosslinking PE (polyethylene) by gammairradiation in 1971 for their SOM hip implants. Since then, they havestudied the effect of a wide range of sterilization doses up to 1,000MegaRad (MRad) on the mechanical, thermal, and wear properties ofUHMWPE. They have also studied the effects of different interfacematerials on wear and found that alumina or zirconia heads on 200 MRadirradiated UHMWPE liners produced the lowest wear rates (Oonishi, H. etal., Radiat. Phys. Chem., 39(6), 495, 1992; Oonishi, H. et al., Mat.Sci: Materials in Medicine, 7, 753-63, 1966; Oonishi, H. et al., J. Mat.Sci: Materials in Medicine, 8, 11-18, 1997).

[0029] Massachusetts General Hospital/Massachusetts Institute ofTechnology (MGH/MIT) has used irradiation (especially e-beam) treatmentsto crosslink UHMWPE. These treatments reduced simulator wear rates ofhip components by 80 to 95% in comparison to non-sterilized controls(see, e.g., World Patent Application 97/29793). This technology enablesUHMWPE to be crosslinked to a high degree; however, the degree ofcrosslinking is dependent upon whether the irradiated UHMWPE is in asolid or molten state. Massachusetts General Hospital/MassachusettsInstitute of Technology (MGH/MIT) has also disclosed the crosslinking ofUHMWPE at greater than about 1 MRad, preferably greater than about 20MRad to reduce the production of fine particles (U.S. Pat. No.5,879,400). They disclosed a wear rate of 8 mg/million cycles for theunirradiated pin and 0.5 mg/million cycles for the irradiated (20 MRad)UHMWPE pin.

[0030] Orthopaedic Hospital/University of Southern California hasdisclosed patent applications which seek to increase the wear resistanceof UHMWPE hip components using irradiation followed by thermaltreatment, such as remelting or annealing (World Patent Application WO98/01085). Irradiation of the UHMWPE was disclosed at 1-100 MRad, morepreferably 5-25 MRad, and most preferably 5-10 MRad. Wear rates weredisclosed for various doses of irradiation. Using this method, UHMWPEcrosslinking was optimized such that the physical properties were aboveASTM limits.

[0031] In U.S. Pat. No. 6,165,220, McKellop et al., has disclosed thecrosslinking of UHMWPE at 1-25 MRad, more preferably 1-15 MRad, and mostpreferably 10 MRad. Oxidation profiles were given for UHMWPE crosslinkedwith 5, 10, or 15 MRad. They did not look at the size or number of wearparticles.

[0032] BMG's European Application (EP 0729981 A1) discloses a uniqueprocessing method for decreasing friction and abrasive wear of UHMWPEused in artificial joints. The method involves irradiating UHMWPE at alow dose to introduce a small number of crosslinking points. Irradiationis followed by uniaxial compression of melted material to achievemolecular and crystallite orientation. BMG's material demonstrated asignificant reduction in pin-on-disk wear, but the reduction was not assignificant as with highly crosslinked versions of UHMWPE (Oka, M. etal., “Wear-resistant properties of newly improved UHMWPE,” Trans. 5^(th)World Biomaterials Congress, 520, 1996).

[0033] In U.S. Pat. No. 6,017,975, Saum et al., has disclosed thecrosslinking of UHMWPE at 0.5-10 MRad, and more preferably 1.5-6 MRad toimprove wear properties. They determined the wear rate for MRad up to 5MRad but did not look at the size and number of wear particles.

[0034] Yamamoto et al. discloses an analysis of the wear mode andmorphology of wear particles from crosslinked ultrahigh molecular weightpolyethylene. The ultrahigh molecular weight polyethylene wascrosslinked at 0-150 MRad gamma irradiation. Yamamoto et al. stated thatthe size of both cup surface fibrils and wear debris decrease inproportion to the dose of gamma irradiation. (Yamamoto et al., Trans.6^(th) World Biomaterials Congress, 485, 2000).

[0035] Importantly, for these methods, thermal annealing of the polymerduring or after irradiation causes the free radicals (generated duringirradiation) to recombine and/or form a more highly crosslinkedmaterial. Reducing or quenching free radicals is extremely importantbecause a lack of free radicals can prevent significant UHMWPE aging.

[0036] B. Chemical Crosslinking

[0037] Like irradiation crosslinking, chemical crosslinking of UHMWPEhas been investigated as a method for increasing wear resistance.Chemical crosslinking provides the benefit of crosslinking whileavoiding the degradative effects of ionizing irradiation.

[0038] The Orthopaedic Hospital/University of Southern California hassubmitted patent applications for crosslinking UHMWPE in order toincrease wear resistance in orthopaedics (European Patent Application EP0722973 A1), including a method wherein the crosslinking results in amaterial with a decreased crystallinity. Crosslinking is accomplished byirradiation in a molten state or photo crosslinking in a molten state,or crosslinking with a free radical generating chemical, and annealingthe crosslinked polymer to pre-shrink it. Residuals from the chemicalcrosslinking reaction, however, are a regulatory concern and maycontribute to long-term oxidative degradation.

[0039] It remains an object of the present invention, therefore, toprovide a process for treating UHMWPE for use in orthopaedic implantssuch that the long-term wear properties of the UHMWPE are improved.

[0040] It is another object of the present invention to provide aprocess for treating UHMWPE for use in orthopaedic implants in vivo suchthat the performance of the implants in situ is improved.

[0041] It is well known in the published clinical literature that fine(micrometer and sub-micrometer sized) wear debris produced from bearingarticulation of orthopaedic implants can elicit a macrophagecell-mediated response in the host body, which eventually leads toaseptic loosening of the implants and need for revision surgery. Ingeneral, bearing couples are formed from a combination of a softmaterial-ultra high molecular weight polyethylene (UHMWPE)-articulatingagainst a hard material—metal or ceramic. It is the soft UHMWPE materialwhich suffers the predominant wear in this soft-on-hard wear couple.Improvements in the wear resistance of UHMWPE, therefore, are expectedto reduce the generation of fine particulate debris during articulation.

[0042] Although related art explicitly acknowledges the role particulatewear debris in the cell-mediated cascade which ultimately leads toaseptic loosening and revision surgery, it only anticipates a one-to-onerelationship between improvements in gravimetric wear resistance andreduction in wear particulate debris numbers. The art explicitly orimplicitly assumes a reduction in gravimetric wear will result in aconcomitant reduction in the generation of wear particles. The teachingsof the art do not necessarily result in the desired reductions in thegeneration of wear particles.

[0043] The prior art teaches that increased crosslinking energycorresponds to a decreased gravimetric wear. It presumes that thiscorresponds to a decrease in the number of wear particles. It alsopresumes that this corresponds to a decrease in the biological reactionto the wear debris produced, which may be false. The inventors of thepresent invention have found that decreased gravimetric wear does notnecessarily correlate with decreased particle number and therefore maynot correlate to decreased biological reaction. The present inventionillustrates that there is not a continuum between crosslinking energydose and the generation of wear particles.

[0044] The uniqueness of this work is that when crosslinking medicalgrade UHMWPE with gamma irradiation, the art is inadequate in predictinga relationship between the absorbed radiation dose and generation ofwear debris in hip simulator testing. Within the range of acceptabledose, ranging from 5 MRad (significant reduction in gravimetric wear) to15 MRad (acceptable upper limit for material strength considerations),the 10 MRad dose has been shown to fulfill the requirement for reducedwear debris generation. Alternative sources of irradiation (e.g.,electron beam), or other gamma radiation doses between 5 and 15 MRad arepredicted to also reduce the generation of particulate debris.

[0045] Recently, Green et al. (Green et al., 2000) found that smallerUHMWPE particles (0.24 μm) produced bone resorbing activity in vitro ata lower volumetric dose than larger particles (0.45 μm and 1.71 μm).This evidence suggests that finer wear particles may elicit a greatermacrophage response than larger particles. Thus, finer wear debrisgenerated at orthopaedic bearing couples should be fully characterizedto accurately predict macrophage response. This is particularlyimportant for new bearing materials, such as crosslinked UHMWPE, whichhave been reported by Bhambri et al. (Bhambri et al., 1999) to generatesmaller wear particles (mean diameter of less than 0.1 μm) thanconventional UHWMPE liners when tested in a hip simulator.

[0046] Because the cellular response to wear debris has been found to bedependent upon particle number and size, among other factors, theintroduction of a new orthopaedic bearing material should be supportedby an accurate description of wear particle parameters. The presentinvention teaches that filter membranes with very fine pore sizes (atmost 0.05 μm) should be used to isolate UHMWPE wear debris from jointsimulator serum and periprosthetic tissue to ensure an accuratedescription of particle characteristics.

[0047] Prior to the present invention, there was not an accurate way topredict the number and size of wear particles of UHMWPE. There was anassumption in the art the increasing radiation caused decreased wearresistance. The methods used in the art use filters with too large of apore size and, consequently, many of the smaller particles pass throughthe filter and are not detected. A large number of the particles createdby wear of UHMWPE were being missed by the previous detection method.

SUMMARY OF THE INVENTION

[0048] Therefore, it is an objective of the present invention to providemethods and medical implants related to the prevention and decrease ofosteolysis produced by wear of the ultrahigh molecular weightpolyethylene (UHMWPE).

[0049] An embodiment of the present invention is a method for isolatingwear particles from an ultrahigh molecular weight polyethylene (UHMWPE)medical implant for use in the body comprising the steps of:crosslinking the UHMWPE; annealing the UHMWPE machining UHMWPE to forman implant; wear testing the implant; harvesting wear particles; andfiltering the particles using 0.05 μm or smaller pore size filters. Themachining may be performed before crosslinking. The crosslinking may beperformed using electromagnetic radiation or energetic subatomicparticles. The crosslinking may be performed using gamma radiation,e-beam radiation, or x-ray radiation. In another aspect of theinvention, the crosslinking may be performed using chemicalcrosslinking. The crosslinking may be at a dose of greater than five butless than or equal to fifteen MegaRad (MRad) or at a dose of greaterthan five but less than or equal to ten MegaRad (MRad). Annealing may beperformed in the melt stage. In a further aspect of the invention, theannealing may be performed in an inert or ambient environment. Theannealing may be performed below or equal to 150° C. The crosslinkingmay be sufficient to form an implant with a trans-vinylene index ofgreater than or equal to 0.10 or greater than about 0.15 and less thanabout 0.20. In another aspect of the present invention, the annealing isperformed below about 150° C. and above about 140° C. and thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10 or greater than about 0.15 andless than about 0.20. In another aspect, the annealing may be performedat 147° C. The crosslinking may be sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. In another aspect of the presentinvention, the annealing may be performed at 140° C. The crosslinkingmay be sufficient to form an implant with a trans-vinylene index ofgreater than or equal to 0.10 or greater than about 0.15 and less thanabout 0.20. Wear testing may occur on a joint simulator. The jointsimulator may simulate the hip joint or knee joint of a human. The weartesting may occur in vivo. The harvesting may be performed using aciddigestion, base digestion, or enzymatic digestion. The implant may havea polymeric structure with greater than about 300 angstrom lamellarthickness.

[0050] Another embodiment of the present invention is a method ofpreparing an UHMWPE medical implant for use in the body having adecreased wear particle number comprising the steps of: crosslinking theUHMWPE; annealing the UHMWPE; and machining UHMWPE to form an implant;wherein the wear particles that are decreased in number are greater than0.125 μm in diameter. The machining may be performed beforecrosslinking. The crosslinking may be performed using electromagneticradiation or energetic subatomic particles. The crosslinking may beperformed using gamma radiation, e-beam radiation, or x-ray radiation.In another aspect of the invention, the crosslinking may be performedusing chemical crosslinking. The crosslinking may be at a dose ofgreater than five but less than or equal to fifteen MegaRad (MRad) or ata dose of greater than five but less than or equal to ten MegaRad(MRad). Annealing may be performed in the melt stage. In a furtheraspect of the invention, the annealing may be performed in an inert orambient environment. The annealing may be performed below or equal to150° C. The crosslinking may be sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. In another aspect of the presentinvention, the annealing is performed below about 150° C. and aboveabout 140° C. and the crosslinking is sufficient to form an implant witha trans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. In another aspect, the annealingmay be performed at 147° C. The crosslinking may be sufficient to forman implant with a trans-vinylene index of greater than or equal to 0.10or greater than about 0.15 and less than about 0.20. In another aspectof the present invention, the annealing may be performed at 140° C. Thecrosslinking may be sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10 or greater than about 0.15 andless than about 0.20. Wear testing may occur on a joint simulator. Thejoint simulator may simulate the hip joint or knee joint of a human. Thewear testing may occur in vivo. The harvesting may be performed usingacid digestion, base digestion, or enzymatic digestion. The implant mayhave a polymeric structure with greater than about 300 angstrom lamellarthickness.

[0051] Yet another embodiment of the present invention is a method ofdecreasing macrophage response to an UHMWPE medical implant for use inthe body comprising the steps of: performing wear particle analysis; andcrosslinking the UHMWPE at a dose level exhibiting the lowest particlenumber per million cycles of the hip simulator wherein the number ofparticles present was determined using a 0.05 μm or smaller pore sizefilter.

[0052] Still another embodiment of the present invention is a method ofdecreasing macrophage response to an UHMWPE medical implant in the bodycomprising crosslinking UHMWPE prior to implantation in a patientwherein the total volume of wear particles is decreased and the totalnumber of wear particles is decreased. The crosslinking may be performedusing electromagnetic radiation or energetic subatomic particles. In anaspect of the present invention, crosslinking may be performed usinggamma radiation, e-beam radiation, or x-ray radiation or chemicalcrosslinking. In another aspect of the invention, the crosslinking maybe at a dose of greater than five but less than or equal to fifteenMegaRad (MRad) or greater than five but less than or equal to tenMegaRad (MRad).

[0053] Another embodiment of the present invention is a method ofdecreasing macrophage response to an UHMWPE medical implant for use inthe body comprising the steps of: crosslinking the UHMWPE; annealing theUHMWPE; machining UHMWPE to form an implant; wear testing the implant;harvesting wear particles; filtering the particles using 0.05 μm orsmaller pore size filters; characterizing the wear particles;determining the number of particulate debris; and selecting thecrosslinking method for implants that gives the lowest number ofparticulate debris. The machining may be performed before crosslinking.The crosslinking may be performed using electromagnetic radiation orenergetic subatomic particles. The crosslinking may be performed usinggamma radiation, e-beam radiation, or x-ray radiation. In another aspectof the invention, the crosslinking may be performed using chemicalcrosslinking. The crosslinking may be at a dose of greater than five butless than or equal to fifteen MegaRad (MRad) or at a dose of greaterthan five but less than or equal to ten MegaRad (MRad). Annealing may beperformed in the melt stage. In a further aspect of the invention, theannealing may be performed in an inert or ambient environment Theannealing may be performed below or equal to 150° C. The crosslinkingmay be sufficient to form an implant with a trans-vinylene index ofgreater than or equal to 0.10 or greater than about 0.15 and less thanabout 0.20. In another aspect of the present invention, the annealing isperformed below about 150° C. and above about 140° C. and thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10 or greater than about 0.15 andless than about 0.20. In another aspect, the annealing may be performedat 147° C. The crosslinking may be sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. In another aspect of the presentinvention, the annealing may be performed at 140° C. The crosslinkingmay be sufficient to form an implant with a trans-vinylene index ofgreater than or equal to 0.10 or greater than about 0.15 and less thanabout 0.20. Wear testing may occur on a joint simulator. The jointsimulator may simulate the hip joint or knee joint of a human. The weartesting may occur in vivo. The harvesting may be performed using aciddigestion, base digestion, or enzymatic digestion. The implant may havea polymeric structure with greater than about 300 angstrom lamellarthickness. In another embodiment of the invention, the characterizationmay be by a high resolution microscopic method or an automatic particlecounter. In a further aspect of the present invention, thecharacterization may be by scanning electron microscopy or automaticparticle counter.

[0054] Yet another embodiment of the present invention is a method ofdecreasing macrophage response to an UHMWPE medical implant for use inthe body comprising the steps of: crosslinking the UHMWPE; annealing theUHMWPE; machining UHMWPE to form an implant; wear testing the implant;harvesting wear particles; filtering the particles using 0.05 μm orsmaller pore size filters; characterizing the wear particles;determining the number of particulate debris; determining the totalparticle surface area; and selecting the crosslinking method forimplants that gives the lowest total particle surface area. Machiningmay be performed before said crosslinking.

[0055] Still another embodiment of the present invention is a method ofdecreasing osteolysis of an UHMWPE medical implant for use in the bodycomprising the steps of: crosslinking the UHMWPE; annealing the UHMWPE;machining UHMWPE to form an implant; wear testing the implant;harvesting wear particles; filtering the particles over 0.05 μm orsmaller pore size filters; characterizing the wear particles;determining the number of particulate debris; and selecting thecrosslinking dose level to crosslink implants that exhibits the lowestnumber of particulate debris. The machining may be performed beforecrosslinking. The crosslinking may be performed using electromagneticradiation or energetic subatomic particles. The crosslinking may beperformed using gamma radiation, e-beam radiation, or x-ray radiation.In another aspect of the invention, the crosslinking may be performedusing chemical crosslinking. The crosslinking may be at a dose ofgreater than five but less than or equal to fifteen MegaRad (MRad) or ata dose of greater than five but less than or equal to ten MegaRad(MRad). Annealing may be performed in the melt stage. In a furtheraspect of the invention, the annealing may be performed in an inert orambient environment. The annealing may be performed below or equal to150° C. The crosslinking may be sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. In another aspect of the presentinvention, the annealing is performed below about 150° C. and aboveabout 140° C. and the crosslinking is sufficient to form an implant witha trans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. In another aspect, the annealingmay be performed at 147° C. The crosslinking may be sufficient to forman implant with a trans-vinylene index of greater than or equal to 0.10or greater than about 0.15 and less than about 0.20. In another aspectof the present invention, the annealing may be performed at 140° C. Thecrosslinking may be sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10 or greater than about 0.15 andless than about 0.20. Wear testing may occur on a joint simulator. Thejoint simulator may simulate the hip joint or knee joint of a human. Thewear testing may occur in vivo. The harvesting may be performed usingacid digestion, base digestion, or enzymatic digestion. The implant mayhave a polymeric structure with greater than about 300 angstrom lamellarthickness. In another embodiment of the invention, the characterizationmay be by a high resolution microscopic method or an automatic particlecounter. In a further aspect of the present invention, thecharacterization may be by scanning electron microscopy or automaticparticle counter.

[0056] Another embodiment of the present invention is a method ofdecreasing osteolysis of an UHMWPE medical implant for use in the bodycomprising the steps of: crosslinking the UHMWPE; annealing the UHMWPE;machining UHMWPE to form an implant; wear testing the implant;harvesting wear particles; filtering the particles using 0.05 μm orsmaller pore size filters; characterizing the wear particles;determining the number of particulate debris; determining the totalparticle surface area; and selecting the crosslinking method forimplants that gives the lowest total particle surface area. Machining isperformed before said crosslinking.

[0057] Yet another embodiment of the present invention is a method ofdecreasing macrophage response to a UHMWPE medical implant for use inthe body comprising the steps of crosslinking the UHMWPE, simulating usein a host, and testing serum for particulate debris using a 0.05 μm poresize filter, wherein particles of the diameter of 0.1 μm to 1 μm causeincreased macrophage response. The machining may be performed beforecrosslinking. The crosslinking may be performed using electromagneticradiation or energetic subatomic particles. The crosslinking may beperformed using gamma radiation, e-beam radiation, or x-ray radiation.In another aspect of the invention, the crosslinking may be performedusing chemical crosslinking. The crosslinking may be at a dose ofgreater than five but less than or equal to fifteen MegaRad (MRad) or ata dose of greater than five but less than or equal to ten MegaRad(MRad). Wear testing may occur on a joint simulator. The joint simulatormay simulate the hip joint or knee joint of a human.

[0058] Still another embodiment of the present invention is acrosslinked UHMWPE medical implant for use in the body that exhibitsdecreased osteolysis (or macrophage response) in comparision toconventional treatment of UHMVVPE due to a particle number of less than5×10¹² per year upon testing for wear resistance.

[0059] Another embodiment of the present invention is an UHMWPE medicalimplant for use in the body having a decreased wear particle number ofparticles created by the steps comprising of: crosslinking the UHMWPE;annealing the UHMWPE; machining UHMWPE to form an implant; wear testingthe implant; harvesting wear particles; filtering the particles over0.05 μm or smaller pore size filters; characterizing the wear particles;determining the number of particulate debris; and selecting thecrosslinking method to crosslink implants that exhibits the lowestnumber of particulate debris; wherein the wear particles that aredecreased in number are greater than 0.125 μm in diameter. The machiningmay be performed before crosslinking. The crosslinking may be performedusing electromagnetic radiation or energetic subatomic particles. Thecrosslinking may be performed using gamma radiation, e-beam radiation,or x-ray radiation. In another aspect of the invention, the crosslinkingmay be performed using chemical crosslinking. The crosslinking may be ata dose of greater than five but less than or equal to fifteen MegaRad(MRad) or at a dose of greater than five but less than or equal to tenMegaRad (MRad). Annealing may be performed in the melt stage. In afurther aspect of the invention, the annealing may be performed in aninert or ambient environment. The annealing may be performed below orequal to 150° C. The crosslinking may be sufficient to form an implantwith a trans-vinylene index of greater than or equal to 0.10 or greaterthan about 0.15 and less than about 0.20. In another aspect of thepresent invention, the annealing is performed below about 150° C. andabove about 140° C. and the crosslinking is sufficient to form animplant with a trans-vinylene index of greater than or equal to 0.10 orgreater than about 0.15 and less than about 0.20. In another aspect, theannealing may be performed at 147° C. The crosslinking may be sufficientto form an implant with a trans-vinylene index of greater than or equalto 0.10 or greater than about 0.15 and less than about 0.20. In anotheraspect of the present invention, the annealing may be performed at 140°C. The crosslinking may be sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10 or greater thanabout 0.15 and less than about 0.20. Wear testing may occur on a jointsimulator. The joint simulator may simulate the hip joint or knee jointof a human. The wear testing may occur in vivo. The harvesting may beperformed using acid digestion, base digestion, or enzymatic digestion.The implant may have a polymeric structure with greater than about 300angstrom lamellar thickness. In another aspect of the invention, thecharacterization may be by a high resolution microscopic method or anautomatic particle counter. In a further aspect of the presentinvention, the characterization may be by scanning electron microscopyor automatic particle counter.

[0060] As used herein the specification, “a” or “an” may mean one ormore. As used herein in the claim(s), when used in conjunction with theword “comprising”, the words “a” or “an” may mean one or more than one.As used herein “another” may mean at least a second or more.

[0061] Other objects, features and advantages of the present inventionwill become apparent from the following detailed description. It shouldbe understood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF SUMMARY OF THE DRAWINGS

[0062] The following drawings form part of the present specification andare included to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein:

[0063]FIG. 1. SEM micrographs at 10,000× of (a) digested and filtereddeionized water and (b) digested and filtered knee simulator serum.

[0064]FIG. 2. Number of particles per field vs. measured UHMWPE wear forsimulator-tested tibial inserts.

[0065]FIG. 3. Average particle volume per field (VFIELD) VS. UHMWPE wearfor simulator-tested tibial inserts.

[0066]FIG. 4. Fourier transform infrared spectra of particles recoveredfrom serum, HDPE reference material, and the KBr background.

[0067]FIG. 5. Scanning electron micrograph of wear debris isolated fromhip simulator serum and recovered on a 0.2 μm pore size filter membrane.

[0068]FIG. 6. Scanning electron micrograph of wear debris isolated fromhip simulator serum and recovered on a 0.05 μm pore size filtermembrane.

[0069]FIG. 7. Size distribution of the particles recovered on the 0.2 μmpore size filter membranes.

[0070]FIG. 8. Size distribution of the particles recovered on the 0.05μm filter pore size membranes.

[0071]FIG. 9. Particles generated per million cycles using 0.2 μmfiltration.

[0072]FIG. 10. Particles generated per million cycles using 0.05 μmfiltration.

[0073]FIG. 11. SEM micrographs of UHMWPE particles extracted from serum

[0074]FIG. 12. Particle number vs. size histogram.

[0075]FIG. 13. Particle volume vs. size histogram.

[0076]FIG. 14. Trans-vinylene indices for gamma-irradiated andsubsequently annealed UHMWPE.

DETAILED DESCRIPTION OF THE INVENTION

[0077] Definitions

[0078] Annealing, as used herein, refers to heating a sample, such asUHMWPE, and then allowing the sample to cool. Thermal annealing of thesample during or after irradiation causes the free radicals (generatedduring irradiation) to recombine and/or form a more highly crosslinkedmaterial.

[0079] Characterizing the wear particles, as used herein, refers todetermining the size, shape, number, and concentration of the wearparticles. It may include the use of, but is not limited to, using amicroscopic method such as scanning electron microscopy, or an automaticparticle counter.

[0080] Decreased or increased, as used herein, refers to a decrease orincrease in a parameter in comparison to that parameter in conventional(not crosslinked) polyethylene.

[0081] Dose, as used herein, refers to the amount of radiation absorbedby the sample, such as UHMWPE.

[0082] Gravimetric, as used herein, refers to the measuring of weightloss.

[0083] In vivo, as used herein, refers to an activity occurring withinthe body of a subject, preferably a human subject.

[0084] Lamellar thickness, as used herein, is the depth of the layers ofalternate amorphous and crystalline regions. The lamellar thickness (1)is the calculated thickness of assumed lamellar structures in thepolymer using the following expression:

l=(2T·σ_(e) ·T _(m) ^(o))/(ΔH(T _(m) ^(o) −T _(m))ρ)

[0085] where σ_(e) is the end free surface energy of polyethylene(2.22×10⁻⁶ cal/cm²), ΔH is the heat of melting of polyethylene crystals(69.2 cal/g), ρ is the density of the crystalline regions (1.005 g/cm³),and T_(m) ^(o) is the melting point of a perfect polyethylene crystal(418.15 K).

[0086] Macrophage response, as used herein, refers to an adversereaction that may lead to osteolysis of an implant.

[0087] MegaRad (MRad), as used herein, refers to a unit of measure forthe energy absorbed per unit mass of material processed by irradiation(absorbed dose). The radiation dose may be within an error of ±10%. AMegaRad is equivalent to 10 kiloGray (kGy).

[0088] Osteolysis, as used herein, refers to the reabsorption of bone.

[0089] Trans-vinylene index (TVI), as used herein, is a based upon theconcentration of trans-vinylene units (TVU) which have been shown to belinear with absorbed radiation dose for polyethylene at low dose levels.The concentration of TVU and thus the TVI, can be used to determine thelevel of crosslinking in UHMWPE. It can be used to determine theabsolute dose level received during the crosslinking of UHMWPE. The TVIis calculated by normalizing the area under the trans-vinylene vibrationat 965 cm⁻¹ to that under the 1900 cm⁻¹ vibration.

[0090] Ultra high molecular weight polyethylene, as used herein, refersto polyethylene having a molecular weight greater than 1.75 million.

[0091] Wear debris, as used herein, refers to particles generated fromthe articulation of the joint components.

[0092] Wear resistance, as used herein, refers to the property ofresisting physical changes in the material due to articulation.

[0093] Wear testing, as used herein, articulating joint components. Weartesting includes testing in water, synovial fluid, or any lubricant.

[0094] Crosslinked ultrahigh molecular weight polyethylene (UHMWPE) andimplants are useful as prostheses for various parts of the body, such ascomponents of a joint in the body. For example, in the hip joints, theycan be a prosthetic acetabular cup (as exemplified above), or the insertor liner of the cup, or a component of a trunnion bearing (e.g. betweenthe modular head and the stem). In the knee joint, they can be aprosthetic tibial plateau (femoro-tibial articulation), patellar button(patello-femoral articulation), and trunnion or other bearingcomponents, depending on the design of the artificial knee joint. Forexample, in knees of the meniscal bearing type, both the upper and lowersurfaces of the UHMWPE component may be surface-crosslinked, i.e., thosesurfaces that articulate against metallic or ceramic surfaces. In theankle joint, they can be the prosthetic talar surface (tibio-talararticulation) and other bearing components. In the elbow joint, they canbe the prosthetic radio-humeral joint, ulno-humeral joint, and otherbearing components. In the shoulder joint, they can be used in theglenoro-humeral articulation, and other bearing components. In thespine, they can be used in intervertebral disk replacement and facetjoint replacement. They can also be made into temporo-mandibular joint(jaw) and finger joints. The above are by way of example, and are notmeant to be limiting. This application often uses UHMWPE and acetabularcup inplants as examples of UHMWPE and implants, respectively. However,it is to be understood that the present invention would be applicable toPE in general; and to implants in general.

[0095] Osteolysis is a common long-term complication in total hipreplacement (THR) (Harris, 1995) and has been linked to wear debrisgenerated from ultra high molecular weight polyethylene (UHMWPE)acetabular liners (Amstutz et al., 1992; Schmalzried et al., 1992;Willert et al., 1990; and Goldring et al., 1983). While the response ofperiprosthetic tissue to wear debris is not fully understood, macrophageresponse to particulate wear debris is believed to be an importantfactor in osteolysis (Goodman et al., 1998; Jasty et al., 1994; Chiba etal., 1994; and Jiranek et al., 1993). It is well established that thecellular response to wear debris is dependent upon particle number,shape, size, surface area, and material chemistry, among other factors(Green et al., 1998; Gonzalez et al., 1996; and Shanbhag et al., 1994).The introduction of new bearing materials, such as crosslinked UHMWPE,should therefore be supported by accurate descriptions of the number,size distribution, surface area, and volume of wear particles generated.

[0096] Various techniques have been developed to isolate UHMWPE wearparticles from periprosthetic tissue and joint simulator serum. Commonprotocols involve digestion of tissue or serum samples in either astrong base or acid, followed by filtration of the digests throughfilter membranes with a pore size of 0.2 μm (McKellop et al., 1995;Campbell et al., 1995; and Niedzwiecki et al., 1999). A scanningelectron microscope (SEM) is used to determine the numbers, sizes, andshapes of particles deposited on the filter membrane. Previous analysesof particles recovered from the periprosthetic tissues of THR patientsand from hip simulator serum indicated that the mode of the particlesize distribution was at or below the pore size (0.2 μm) of the filtermembrane (McKellop et al., 1995). Thus, a significant number ofparticles having a diameter below 0.2 μm may have passed through thefilter pores and not been detected during the analyses. It is thereforehypothesized that the number of UHMWPE particles generated by THRbearing components are underestimated by particle isolation techniqueswhich involve filtration of debris through a 0.2 μm filter membrane.

[0097] In the present invention, hip simulator testing was conducted onthree classes of materials (1) conventional (non-irradiated) UHMWPE(C-PE), (2) 5 MRad gamma irradiation crosslinked UHMWPE (5-XLPE), and(3) 10 MRad gamma irradiation crosslinked UHMWPE (10-XLPE). According topublished literature, 5-XLPE and 10-XLPE are both expected to exhibitenhanced wear resistance compared to C-PE, with the degree ofimprovement increasing with increasing radiation dose. Gravimetricanalyses showed the expected trends to hold up to a duration of 15million cycles tested to-date. However, when analyzed for particulatedebris, it was discovered that the 5-XLPE material began to generatemore wear debris than C-PE approximately at approximately 5 millioncycle. The 10-XLPE material, on the other hand, showed fewer particlesfor the entire duration of testing. Crosslinking affects the size ofparticles. It is ideal to decrease the total volume of particles and thenumber of particles at all sizes.

[0098] Crosslinking of UHMWPE

[0099] The wear process in an artificial joint is a multi-directionalprocess. Crosslinking is achieved by using high doses of radiation. Inthe absence of oxygen, crosslinking is the predominant effect ofionizing radiation on UHMVVPE (Rose et al., 1984, Streicher et al.,1988). Crosslinking of UHMWPE forms covalent bonds between polymerchains which inhibit cold flow (creep) of individual polymer chains.Crosslinking UHMWPE provides a lower wear rate because the polymerchains form a network that is more stable to multi-directionalmovements. When irradiated at temperatures above 150° C., a permanentintermolecular homogeneous network is formed. Exposure of UHMWPE toirradiation results in the cleavage of carbon-carbon and carbon-hydrogenbonds within the polyethylene chains. Such irradiation includes but isnot limited to energetic subatomic particles, gamma, electron beam, orx-ray radiation. Gamma irradiation is known to break polymer chains andcreate free radicals, that react with oxygen in the atmosphere orsynovial fluid. This oxidation reaction causes further chain scissionand leads to the formation of an embrittled region close to the polymersurface (Buchanan et al., 1998, Materials Congress 1998, p.148).Oxidation of free radicals formed during irradiation leads to areduction in molecular weight, and subsequent changes in physicalproperties, including wear resistance. Formation of free radicals duringirradiation primarily include a combination of alkyl and allyl type freeradicals. In the presence of oxygen, however, a small fraction of peroxyradicals are also formed. To reduce the formation of peroxy radicals,the process is performed under vacuum or in the presence of an inertgas, such as argon. Free radicals can be removed through either additionof antioxidants or through remelting. Remelting is a process in whichthe implants are reheated to increase chain mobility, so the freeradicals can recombine or terminate. The overall industrial process isto radiate polymer sheets, which are remelted. From the remelted sheetsimplants are machined and thereafter sterilized.

[0100] It is well known in the art that crosslinking of UHMWPE by anumber of means, including irradiation with energetic beams (gamma rays,electron beams, x-rays, etc.,) or by chemical means improves the wearresistance of the material. Although clinical use of crosslinked UHMWPEwas first reported in the 1970's it was not until the mid 1990's thatanatomic joint (hip and knee) simulator tests were conducted todemonstrate the enhanced wear resistance of crosslinked UHMWPE. Theextant literature and art teaches methods by which UHMWPE can becrosslinked to varying degrees and demonstrates improvements in wearresistance in joint simulator testing.

[0101] The present invention includes all forms of crosslinking,crosslinking at all temperatures, crosslinking in the presence orabsence of an inert environment, and in the presence or absence offree-radical scavengers. Crosslinking may occur before or after theimplant is formed (machined).

[0102] Macrophage Response and Osteolysis

[0103] The major cause of late-term implant failure is implant inducedosteolysis and aseptic loosening of hip replacements. Osteolysis is thereabsorption of bone, in this case due to a reaction to polyethylenewear debris. The majority of wear particles produced by implants arethought to be submicron in size. Patient tissue examined in revisionoperations show a periprosthetic pseudo-membrane containing macrophagesand multinucleated giant cells (osteoclasts, which can be viewed asspecialized macrophages) associated with polyethylene particles. Thewear debris stimulates macrophages to produce mediators of osteolysiswhich causes aseptic loosening of the implant. Mediators produced by themacrophages include IL-1β, IL-6, TNFα, GM-CSF, PGE₂, and enzymes such ascollagenase. IL-6 stimulates the formation of osteoclasts and thusstimulates bone resorption. IL-1β stimulates proliferation andmaturation of progenitor cells into osteoclasts. IL-1β also stimulatesosteoblasts causing maturation of the osteoclast into multinucleate bonereabsorbing cells. TNFα has much the same function as IL1β in thissituation (Green et al., 1998). The ruffled border of osteoclastsreleases acids and hydrolytic enzymes that dissolve proteins andminerals. Osteoblasts create bone by synthesizing proteins. Osteoblastssecrete collagenase, which may facilitate osteoclast activation.Osteoblasts produce TGFβ, IGF1, IGF2, PDGF, IL1, FGF, TNFα that regulategrowth and differentiation of bone (Pathology, Rubin, Second Ed. 1994;Essential Medical Physiology, Johnson, 1992). The biological activity ofpolyethylene wear debris is dependent upon the size and number ofparticles present (Matthews et al., 2000 Biomaterials, p. 2033).Matthews et al. found particles of the size 0.24, 0.45, and 1.7 μm to bethe most biologically active. This finding was based on cell studies inwhich the wear debris was filtered over 10, 1.0, 0.4, and 0.1 μm poresize filters. Wear particles were co-cultured with donor macrophages andthe production of mediators was measured. The specific biologicalactivity (SBA) of the wear debris is calculated using the equation:

SBA=[B(r)×C(c)]_(0.1-1.0 μm) +[B(r)×C(c)]_(1-10 μm)+[B(r)×C(c)]_(10 -100 μm)

[0104] Where B(r) is the biological activity function of a givenparticle size and C(c) is the volumetric concentration of the weardebris for a given particle size. The functional biological activity(FBA) is the product of the wear volume and the SBA (Fisher et al., 200046^(th) ORS Meeting).

[0105] Methods of Wear Analysis

[0106] Joint simulator wear testing of orthopaedic bearing componentsreproduces in vivo wear mechanisms. A common means of verifying thereproduction of clinical wear mechanisms is to compare the wear debrisof laboratory and retrieved specimens (McKellop et al., 1995). UHMWPEdebris can be isolated from both retrieved periprosthetic tissue andsimulator-tested serum using a method developed by Campbell et al.(Campbell et al., 1995). This widely accepted method uses base digestionof the serum, centrifugation, and density gradients to isolate UHMWPEdebris. However, the process is labor intensive and expensive. Analternative method for isolating UHMWPE wear debris fromsimulator-tested serum includes an acid treatment and vacuum filtrationto isolate particles (Scott et al., 2000). Collected wear debris canthen be mounted, sputter coated with gold, and analyzed by scanningelectron microscopy (SEM). SEM can be used to determine the numbers,size, and shapes of particles. FTIR spectra of the debris can becompared with those of a control substance, such as HDPE, to determinethe identity of the wear debris.

[0107] Gravimetric Measurement

[0108] Wear resistance can also be defined and determined by gravimetricmeans, by measuring the weight loss of the UHMWPE component at fixedintervals of the test duration. Gravimetric measurement provides thechange in weight from before testing to after testing. The gravimetricwear rate is defined in milligrams/million cycles of the simulator. Itprovides a measurement of the total mass of debris generated from wearsurfaces. It does not give any information regarding the size and numberof wear particles. This method is not accurate when the material absorbsfluid. UHMWPE does absorb fluid. It was previously believed thatgravimetrically measured reduction in wear translated into reduction inparticle generation. Thus, it was assumed that a decrease in weight losscorrelated with decreased wear and decreased particle characteristics.Therefore, it would be expected that there would be a decrease inosteolysis as well. There is no predictable relationship between totalwear mass and particulate number. This is explained by the followingequation:$V_{{total}\quad {wear}} = {\sum\limits_{i = 1}^{N}V_{{each}\quad {particle}}}$

[0109] where N is the number of particles. For instance, if crosslinkingreduces the average volume of individual particles, then a greaternumber of particles will be produced per unit volume of total wear. Onthe other hand, if crosslinking increases the average particle volume,then there are fewer particles per unit volume of total wear. Thus,particle size dictates the number of particles produced per unit volumeof total wear. Gravimetric methods cannot measure individual particleparameters such as size, volume and number. Thus, gravimetric techniquesare limited and do not provide a means to measure and evaluate theseindividual particle characteristics.

[0110] Joint Simulators

[0111] Joint simulators include hip simulators, knee simulators andother joint simulators. In one use of a hip simulator, UHMWPE acetabularliners are articulated against CoCrMo heads. Commercially availableacetabular liners are machined from ram-extruded UHMWPE and sterilizedusing ethylene oxide. The liners were inserted into Ti-6A1-4V acetabularshells and tested against 32 mm diameter CoCr femoral heads. The bearingcouples are tested under physiological loading and motion conditions(Bergmann et al., 1993; Johnston and Schmidt, 1969; and ISO/CD14242-1.2) on a 12-station hip simulator. Test duration can range from 1million to 30 million cycles (Mcycles) at a cyclic frequency of 1 Hz,representing 1 to 30 years of normal service in the human host. The testlubricant is bovine serum containing 0.2% sodium azide and 20 mM EDTA.The test serum is replaced approximately every 500,000 cycles.

EXAMPLES

[0112] The following examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those skilledin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents that are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

Example 1 Validation of an Acid Digestion Method for Isolating UHMWPEWear Debris from Joint Simulator Serum

[0113] The particle isolation method was performed on the followingsamples: (1) deionized water; (2) untested bovine calf serum; (3)deionized water pumped through silicone tubing at 37° C. for one week;and (4) simulator-tested serum from four separate stations on an AMTIknee simulator. The sera from the knee simulator were harvested at about500,000 cycles and contained between 1 and 20 mg of UHMWPE debris (asdetermined by weight loss of UHMWPE tibial inserts). Ten ml of eachsample was added to 40 ml of 37% HCl. A magnetic stir bar was added tothe solution and stirred at 350 rpm at 50° C. for approximately onehour. At this time, 1 ml of the solution was removed and added to 100 mlof methanol. This solution was then filtered through a 0.2 μm pore sizepolycarbonate filter membrane. The filter membranes were mounted onmetal microscope stubs, sputter coated with gold, and imaged using ascanning electron microscope (SEM). Image analysis was performed at10,000× in order to determine contamination levels (“blank” samples 1though 3) and to correlate observed wear with particle count density(simulator-tested sera). For each of the simulator-tested samples, aminimum of 500 particles and 20 fields of view were analyzed, and theparticle count density was expressed in average number of particles perfield. Additionally, the average particle volume per field (VFIELD) wascalculated by dividing the total volume of analyzed particles in asample by the number of fields needed to image all the particles. Thevolume of each particle was estimated using the following equation:

V _(PARTICLE)=4/3 π(ECR),

[0114] where ECR is the radius of a circle having the same area as themeasured feature.

[0115] A representative SEM image of the filter membrane through whichthe digested deionized water sample was passed is shown in FIG. 1a. At10,000×, no particles were seen on the filter membrane, indicating anabsence of contaminants within the reagents used in the procedure. Thefilter membrane through which the digested untested serum was passed hada similar appearance, indicating that the proteins in the serum werecompletely digested by the HCl. Filtration of the water sample that waspumped through silicone tubing also resulted in an absence of particles.This suggests that the tubing though which serum is circulated in jointsimulators releases insignificant levels of silicone debris. Thedigested sera from the knee simulator showed particulate material thatwas comprised of two predominant morphologies, spheroids and fibrils(FIG. 1b).

[0116] Quantitative image analysis revealed that the number of particlesper field correlated strongly (R²=0.997) with measured UHMWPE wear forthe simulator-tested serum samples (FIG. 2). The average particle volumeper field of view also correlated strongly (R²=0.983) with measuredUHMWPE wear (FIG. 3).

Example 2 Hip Simulator Specimens and Parameters

[0117] Commercially available acetabular liners were machined fromram-extruded GUR 1050 UHMWPE (Poly-Hi Solidur, Ft. Wayne, Ind.) andsterilized using ethylene oxide. The liners were inserted into Ti-6A1-4V(ISO 5832) acetabular shells and tested against 32 mm diameter CoCrfemoral heads (ASTM F799). The bearing couples (n=3) were tested underphysiological loading and motion conditions (Bergmann et al., 1993;Johnston and Schmidt, 1969; and ISO/CD 14242-1.2) on a 12-station AMTI(Watertown, MA) hip simulator. Testing was conducted to 12 millioncycles (Mcycles) at a cyclic frequency of 1 Hz. The test lubricant wasbovine serum (Hyclone Laboratories, Logan, Utah) which contained 0.2%sodium azide and 20 mM EDTA. The test serum was replaced approximatelyevery 500,000 cycles.

Example 3 Isolation of UHMWPE Particles

[0118] Eight serum samples were harvested during the 12 million cycletest. The test interval (in cycles) for each serum sample is listed inTable 1. Each sample was collected in an Erlenmeyer flask containing astirbar and stirred overnight at 350 rpm. Ten ml of serum was then addedto 40 ml of 37% w/V HCl and stirred for one hour at 50° C. One ml of thedigested solution was added to 100 ml of methanol, which was thenfiltered through a 0.2 μm pore size polycarbonate filter membrane. Areplicate digest was filtered through a 0.05 μm pore size membrane foreach serum sample. TABLE 1 Data on Serum Samples Harvested from a HipSimulator. N_(F)* N_(F)* N_(C) ^(§) (10⁶) N_(C) ^(§) (10⁶) (0.2 μm (0.05μm (0.2 μm (0.05 μm Serum Testing Interval pore size pore size pore sizepore size Sample (10⁶ cycles) filters) filters) filters) filters) 10.580-1.064 49.6 157.5 2.7 8.7 2 4.021-4.461 48.2 173.5 2.9 10.5 38.006-8.628 54.7 117.9 2.3 5.1 4 9.228-9.717 49.2 98.5 2.7 5.4 510.289-10.837 47.8 137.3 2.3 6.7 6 10.289-10.837 44.7 105.3 2.2 5.1 711.369-11.972 64.9 102.8 2.9 4.5 8 11.369-11.972 54.6 117.1 2.4 5.2Average 51.7 126.2 2.6 6.4 Std. Dev. 6.3 27.4 0.2 2.2

Example 4 Characterization of Particle Size and Number

[0119] Each filter membrane was mounted on an aluminum stub, sputtercoated with gold, and examined using a SEM (S360, Leica, Inc.,Deerfield, IL). Images were taken at a magnification of 10,000× andtransferred to a digital imaging system (eXL II, Oxford Instruments,Ltd., England). A minimum of twenty fields of view were analyzed perfilter membrane. Particle diameter (Dp) was calculated based on theprojected area (A) of each particle. This parameter was based oncircular geometry and calculated as follows:

D _(P)=2 (A/π)^(½)  (1)

[0120] For each filter membrane, the mean number of particles per fieldof view (NF) was determined, and the number of particles generated percycle of testing (Nc) was calculated as follows:

N _(C) =N _(F)(A _(FILTER) /A _(FIELD))d/c  (2)

[0121] where A_(FILTER)=area of filter membrane=962 mm²; A_(FIELD)=areaof field of view=9.0×10⁻⁵=dilution ratio=2500; and c=number of testcycles.

[0122] For each type of filter membrane, the data from the differentdigests were pooled. The particle diameter data were presented as themean, median, mode, and standard deviation. The number of particles percycle was presented as the mean and standard deviation. Significantdifferences (ANOVA; α=0.05) in mean particle parameters were determinedbetween the particles deposited on the 0.2 μm and 0.05 μm pore sizefilter membranes. The Kruskal-Wallis test was used to determinesignificant differences in median particle diameter between the twofilter membranes.

Example 5 Reproducibility of Particle Isolation Method

[0123] For the acid digestion/vacuum filtration method used in thisstudy, a strong linear correlation has been demonstrated betweenmeasured wear volume (as determined gravimetrically) and the volume ofparticles recovered from a total joint simulator (Scott et al., 2000).For digests filtered through a 0.05 μm pore size filter membrane,inter-observer reproducibility has been found to be within 10% of themean value for each of the following parameters: (i) number of particlesgenerated per cycle of testing; and (ii) mean particle diameter (Table2). TABLE 2 Wear Particle Data Demonstrating InterobserverReproduciblity for Two Serum Samples Harvested from a Hip Simulator(Mean ± Std. Dev.). Mean Particle Mean Particle Diameter Diameter SerumN_(F)* N_(F)* (μm) (μm) Sample Observer 1 Observer 2 Observer 1 Observer2 A 123.6 ± 20.8 123.8 ± 45.0 0.11 ± 0.12 0.12 ± 0.14 B  76.3 ± 12.0 78.1 ± 21.2 0.20 ± 0.29 0.22 ± 0.32

Example 6 Verification of Particle Identity

[0124] Fourier transform infrared spectroscopy (FTIR) was performed todetermine the identity of wear debris from three of the serum samples.In each case, approximately one mg of particles was transferred from thefilter membranes onto a KBr disk and identified using a FTIRspectrometer with an attached infrared microscope (FTS165 spectrometer,UMA250 microscope, Bio-Rad Laboratories, Hercules, Calif.). The FTIRspectra of the particles isolated from serum were compared with that ofa commercially available HDPE powder (Shamrock Technologies Inc.,Newark, N.J.).

Example 7 Current Wear Particle Procedure Underestimate the Number ofParticles Generated by Prosthetic Bearing Components

[0125] UHMWPE liners were articulated against CoCrMo heads on ananatomic hip simulator up to 12 million cycles. Serum samples wereperiodically harvested and subjected to a validated acid digestionmethod Scott et al., 2000). Replicate digests were vacuum filteredthrough either a 0.2 μm or 0.05 μm pore size filter membrane. Relativedifferences in the particle number and size distribution were determinedfor each membrane pore size.

[0126] The recovered particles were characterized using Fouriertransform infrared spectroscopy (FTIR) and scanning electron microscopy.The FTIR spectra of the particles recovered from the hip simulator serawere similar to that of the reference HDPE material and consistent withUHMWPE in that they had major peaks around 2917, 2850, 1470, and 721cm⁻¹ (FIG. 4) (Painter et al., 1982). Extraneous peaks and valleys werefound to correspond with the peak positions of the KBr disk. No evidenceof impurities, such as filter material, debris from the tubing throughwhich serum was circulated, or undigested proteins, was found.

[0127] SEM analysis revealed that the recovered wear particles weredistributed uniformly on both types of filter membranes (FIGS. 5 and 6).Minimal agglomeration of particles was observed. The wear particlesdeposited on both the 0.2 μm and 0.05 μm pore size filter membranes werepredominantly submicron and round in appearance. Elongated fibrils (3 to10 μm in length) were occasionally observed on both types of filtermembranes. For the data pooled from all eight serum samples, the totalnumbers of particles imaged on the 0.2 μm and 0.05 μm pore size filterswere 8272 and 20197, respectively. The size distributions for theparticles deposited on the 0.2 μm and 0.05 μm pore size filters arepresented in FIGS. 7 and 8, respectively. The wear particles recoveredon the 0.2 μm and 0.05 μm pore size filter membranes were spatiallydistributed in an uniform manner. Agglomeration of particles wasminimal. Because individual particles were clearly discernable fromother particles and distributed uniformly on the filter membranes,sampling errors were minimized, leading to a more accurate determinationof particle count and size distribution.

[0128] For particles isolated on the 0.2 μm pore size filters, the mean(0.23 μm) of the size distribution was above the specified membrane poresize, whereas the median (0.19 μm) was below the specified pore size.The peak (mode) of the distribution occurred well below the 0.2 μm poresize at 0.13 μm. Over half (52.2%) of the total number of particlesdetected had diameters below the filter pore size of 0.2 μm. For theparticles deposited on the 0.05 μm pore size filters, the mean (0.19 μm)and median mean (0.18 μm) diameters were well above the specifiedmembrane pore size. No single dominant peak occurred in the sizedistribution, with the majority of particles evenly distributed between0.08 and 0.25 μm. Only 2.8 percent of the total particles detected haddiameters below the filter pore size of 0.05 μn. The mean and mediandiameters of the particles deposited on the 0.05 μm membranes weresignificantly lower (p<0.001) than those of particles on the 0.2 μm poresize filter.

[0129] The 0.05 μm pore size filter membranes contained a greater numberof wear particles than the 0.2 μm membranes (Table 1). The mean numberof particles generated per cycle was 6.4×10⁶±2.2×10⁶ for the serumdigests passed through the 0.05 μm pore size filters and was2.6×10⁶±0.2×10⁶ for the digests filtered through the 0.2 μm pore sizemembranes. This difference was statistically significant (p=0.002).

[0130] The use of 0.2 μm pore size membranes caused an underestimate ofthe number of wear particles generated per million cycles for bothconventional and 5 MRad doses of crosslinked UHMWPE (FIG. 9 and FIG.10).

[0131] When vacuum filtration is used to isolate UHMWPE wear debris fromdigested hip simulator serum, the number and size distribution ofrecovered particles is strongly dependent upon the pore size of thefilter membrane. A substantial number of wear particles passed freelythrough the pores of the 0.2 μm pore size membranes. Filtering digestedserum through a 0.2 μm pore size filter underestimates the number, andconsequently the surface area and volume of finer sized particles. Asignificantly greater number of finer sized particles can be isolatedand analyzed by filtering digested serum through a 0.05 μm pore sizefilters. The entire digestion and filtration procedure tookapproximately 75 minutes when the digests were filtered through 0.2 μmpore size filter membranes. Filtering the digests through 0.05 μm poresize filter membranes added only 5 minutes to the procedure with nosignificant increase in the cost of materials and equipment. Thisincrease in procedural time was well justified due to the fact that thenumber of particles recovered from hip simulator serum, and consequentlythe size distribution, was strongly dependent upon the pore size of thefilter membrane used. Fine wear particles have been found to greatlyinfluence the macrophage response to wear debris. This underscores theimportance of using finer pore size (<0.05 μm) filter membranes toisolate and characterize wear debris generated from new orthopaedicbearing materials.

Example 8 Wear Particle Analyses of Conventional and Crosslinked UHMWPETested in an Anatomic Hip Simulator

[0132] Numerous forms of crosslinked UHMWPE, which demonstrate dramaticreductions in hip simulator gravimetric wear, have been developed(McKellop et al., 1999; Muratoglu et al., 1999) and used clinically withthe intent to reduce particle-induced osteolysis. It is generallybelieved that gravimetrically measured reductions in wear translate intoreductions in particle generation. The relationship between gravimetricwear volume and wear particle characteristics (size, surface area, andvolume) was investigated by the comparison of one conventional and twovariations of crosslinked UHMWPE.

[0133] Anatomic hip simulator (AMTI, Watertown, Mass.) tests werecarried out to 10 million cycles on the following materials: (i)conventional UHMWPE (C-PE), (ii) 5 MRad crosslinked UHMWPE (5-XPE), and(iii) 10 MRad crosslinked UHMWPE (10-XPE). Ram extruded GUR 1050material (PolyHi Solidur, Ft. Wayne, Ind.) was the starting material forall tests. Crosslinking was carried out at gamma irradiation doses of 5and 10 MRad (SteriGenics, Gurnee, Ill.), followed by melt annealing (2hrs at 150° C.) and slow cooling. Acetabular liners (32 mm ID) weremachined from bar stock, followed by EtO sterilization. The 5-XPE and10-XPE liners were artificially aged at 70° C. and 5 atm O₂ for 3 weeksprior to testing (Sanford et al, 1995). Hip simulator testing (n=3 foreach group) was carried out against 32 mm CoCrMo heads in 100% bovineserum. The testing was interrupted periodically for weight measurementsand serum replacement. Wear particles were harvested from test serumusing a previously validated acid digestion/vacuum filtration protocol(Scott et al., 2000). The particles deposited on the 0.05-μm pore sizefilter membranes were characterized under a scanning electron microscope(SEM) at magnifications of 1,000× and 20,000×. A minimum of 20 random,non-overlapping fields and 100 particles were imaged to ensure that thedetected particles were representative of the entire particle populationwithin each serum sample. For each material, the mean particle diameterwas determined and the following parameters were calculated per millioncycles: (i) number of particles, (ii) surface area of particles, and(iii) volume of debris generated. Particle diameter, surface area, andvolume were calculated assuming spherical geometry. ANOVA and Duncan'smultiple range tests were used to determine significant differences(α=0.05) in mean particle diameter, number of particles, surface area ofparticles, and volume of debris generated between the materialconditions.

[0134] The gravimetric wear rates decreased as the crosslinkingradiation dose increased. For the C-PE, the wear rate was 36.9mg/Mcycles, which decreased to 9.0 mg/Mcycles for the 5-XPE, whichfurther decreased to −1.1 mg/Mcycles for the 10-XPE (Table 3). Based onSEM micrographs, the C-PE particles were predominantly submicronspheroids, with occasional fibrils 5 to 10 μm in length (FIG. 11). The5-XPE and 10-XPE particles were predominately submicron spheroids (FIG.11).

[0135] In addition to the highest gravimetric wear rate, the C-PEmaterial exhibited the largest particle diameter, surface area, andvolume of debris generated (p<0.05 for all combinations of pairs, Table3). Particle diameter and the surface area and volume of particlesdecreased with increasing crosslinking radiation dose. The 5-XPEmaterial generated the highest number of particles, resulting in twicethe number of particles per Mcycles than C-PE (Table 3). The 10-XPEmaterial generated less than half the number of particles per Mcyclecompared to C-PE. TABLE 3 Gravimetric Wear Rate, Particle Diameter,Surface Area, Volume, and Number for the Tested Materials: Mean ± 95%Confidence Interval C-PE 5-XPE 10-XPE Gravimetric Wear 36.94 ± 0.48 9.02 ± 0.55 −1.11 ± 0.22   Rate (mg/Mcycle) Particle Diameter 0.206 ±0.012 0.118 ± 0.003 0.091 ± 0.003 (μm) Particle Surface 1.17 ± 0.13 0.69± 0.12 0.09 ± 0.02 Area (m²/Mcycle) Particle Volume 95.84 ± 14.69 22.45± 3.45  4.16 ± 1.17 (mm3/Mcycle) Particle Number per 5.76 ± 0.96 12.05 ±1.88  2.28 ± 0.25 Mcycles (1 × 10¹²)

[0136] Increasing the crosslinking radiation dose resulted in a morewear resistant polyethylene as tested in our anatomic hip simulator,consistent with previous reports (McKellop et al., 1999; Muratoglu etal., 1999). The surface area and volume of particles decreased withincreasing radiation dose. Particle size (diameter) also decreased withincreasing radiation dose. Due to different particle size distributions,a unique relationship between gravimetric wear and particle numberexisted for each tested material. As a result, the reduction ingravimetric wear for the 5-XPE material did not translate into areduction in particle number when compared with the C-PE material.

[0137] The mass loss due to wear for the 10-XPE liners was less than thefluid absorption that occurred during testing. As a result, the 10-XPEliners showed a net weight gain. Particle analysis, however, showed thatsmall, but measurable volumes of wear particles were generated. Wearparticle analysis may thus provide a more direct measurement of thevolume and number of particles generated from highly crosslinked UHMWPEand may be used to supplement gravimetric measurements for low wearmaterials.

[0138] Macrophage response to particulate wear debris is believed to bean important factor in osteolysis. It is well established that thecellular response is dependent upon particle number, size, surface area,and material chemistry, among other factors (Shanbhag et al, 1997; Greenet al, 1998; and Gonzalez et al., 1996). Differences in particle number,size, and surface area were observed among conventional and crosslinkedUHMWPE. Thus the biological response to the particulate forms of thesethree materials may differ due to varying particle characteristics.

Example 9 Production of Mediators by Macrophages Exposed to UHMWPEParticles

[0139] Macrophages are isolated using the method of Green et al., 1998.Human macrophages are co-cultured with conventional UHMWPE, 5 MRadcrosslinked UHMWPE, and 10 MRad crosslinked UHMWPE at variousconcentrations. The particles are added to 1% agarose and poured intoplates. Concentrations of particles that are used are 0, 1× the amountof particles detected at 1 million cycles, 2×, 5×, and 10×.Lipopolysaccharide is used as a positive control. Macrophages are thenadded to the top of the plates and incubated at 37° C. for 24 hours. Theamount of IL1-α and TNF-α produced by the macrophages at each particleconcentration is measured by ELISA. IL1-α is assayed using pairedmonoclonal antibodies and TNF-α is measured using a modified doubleantibody sandwich technique.

Example 10 Particle Size Versus Particle Numbers and Volumes forConventional and Crosslinked UHMWPE

[0140] Numerous forms of crosslinked UHMWPE have demonstrated dramaticreductions in hip simulator gravimetric wear. (McKellop et al., 1999;Muratoglu et al., 1999; and Essner et al., 2000). While gravimetrictechniques provide a measurement of the total mass of debris generatedfrom wear surfaces, no information about individual particles is gained.The objectives of this study were to directly determine the number, sizedistribution, and volume distributions for UHMWPE particles generatedduring hip simulator testing. One conventional and two variations ofcrosslinked UHMWPE were compared in this study.

[0141] Anatomic hip simulator (AMTI, Watertown, Mass.) tests werecarried out to 15 million cycles on the following materials: (i)conventional UHMWPE (C-PE), (ii) 5 MRad crosslinked UHMWPE (5-XPE), and(iii) 10 MRad crosslinked UHMWPE (10-XPE). Ram extruded GUR 1050material (PolyHi Solidur, Ft. Wayne, Ind.) was the starting material forall tests. Crosslinking was carried out at gamma irradiation doses of 5and 10 MRad (SteriGenics, Gurnee, Ill.), followed by melt annealing andslow cooling. Acetabular liners (32 mm ID) were machined from bar stockand EtO sterilized. The 5-XPE and 10-XPE liners were artificially agedat 70° C. and 5 atm O₂ for 3 weeks prior to testing (Sanford et al.,1995). Hip simulator testing (n—3 for each group) was carried outagainst 32 mm CoCrMo heads in 100% bovine serum. The testing wasinterrupted periodically for gravimetric measurements and serumreplacement. Wear particles were harvested from test serum using apreviously validated acid digestion/vacuum filtration protocol (Scott etal, 2000). The particles deposited on the 0.05-μm pore size filtermembranes were characterized under a scanning electron microscope (SEM)at magnifications of 1,000× and 20,000×. A minimum of 20 random,non-overlapping fields and 100 particles were imaged to ensure that thedetected particles were representative of the entire particle populationwithin each serum sample. For each detected particle, an equivalentcircular diameter and spherical volume were calculated based theprojected area of the particle. For each material condition, the meannumber of particles generated per cycle (N) of testing was determined.The following distributions were also plotted: (i) particle number vs.diameter and (ii) total particle volume vs. diameter. Total particlevolume was calculated as the sum of individual particle volumescontained within each specified particle diameter interval. ANOVA andDuncan's analyses were used to test for significant differences inparticle generation rates between the material conditions.

[0142] The gravimetric wear rates decreased as the crosslinkingradiation dose increased. For the C-PE, the mean wear rate ±95% CI was36.9±0.5 mg/Mcycles, which decreased to 9.0±0.6 mg/Mcycles for the5-XPE, which further decreased to −0.5±0.2 mg/Mcycles for the 10-XPE.Based on SEM micrographs, the C-PE, 5-XPE, and 10-XPE particles had thesame predominant morphology- submicron granules (FIG. 11). Fibrils 5 to10 μm in length were occasionally seen for the C-PE particles (FIG. 11).

[0143] The 5-XPE material generated the greatest number ofparticles percycle (N=11.1×10⁶±2.5×10⁶), resulting in 78% more particles per cyclethan the C-PE material (N=6.2×10⁶±1.1×10⁶) (p<0.01). The 10-XPE liners(N=2.2×10⁶±0.2×10⁶) generated 65% fewer particles per cycle than theC-PE liners (p<0.01).

[0144] The particle number vs. size distributions for the three materialconditions are presented in FIG. 12. The distributions of total particlevolume vs. size are presented in FIG. 13. Because the three materialsproduced different numbers and volumes of particles over the duration oftesting, the distributions are presented in absolute number instead ofpercent frequency. The 5-XPE liners produced a greater number and volumeof particles below 0.2 μm in diameter than the C-PE liners. Above 0.2μm, the C-PE particles were greater in number and volume of than the5-XPE particles. The C-PE and 10-XPE liners generated an equivalentnumber and volume of particles with diameters less than 0.125 μm. Above0.125 μm, the C-PE particles were greater in number and volume than10-XPE particles.

[0145] Increasing the crosslinking radiation dose resulted in lowergravimetric wear as tested in our anatomic hip simulator, consistentwith previous reports (McKellop et al., 1999; Muratoglu et al., 1999).Increasing radiation dosage also affected the particle sizedistribution, resulting in a unique relationship between gravimetricwear and particle number for each tested material. As a result, thereduction in gravimetric wear for the 5-XPE material did not translateinto a reduction in particle number when compared with the C-PEmaterial.

[0146] In vitro cell culture studies have shown that macrophage responseis a function of particle morphology, size, number, and volumetric dose,among other factors (Shanbhag et al., 1997; Green et al, 2000; andGonzalez et al., 1996). Conventional and two crosslinked UHMWPEmaterials produced particles that were similar in morphology. However,differences in the particle number and volumetric distributions existedbetween the three materials. The 5-XPE material generated the greatestnumber and volume of particles with diameters below 0.2 μm. Above 0.2μm, the C-PE material generated the greatest number and volume ofparticles. For every size interval, the number and volume of 10-XPEparticles were less than or equal to that of the C-PE particles. Arecent cell culture study showed that smaller UHMWPE particles (0.24 μm)produced bone resorbing activity at a lower volumetric dose (10μm³/macrophage), while larger particles (0.45 μm and 1.71 μm) producedbone resorbing activity at doses of 100 μm³ per macrophage (Green et al,2000). Because the particulate forms of the three materials tested haveexhibited different particle size distributions, the biological responseto wear debris from these materials may differ.

EXAMPLE 11 Lamellar Thickness

[0147] Lamellar thickness values were determined using a TA Instruments2910 differential scanning calorimeter (DSC). Testing was conducted perASTM D 3417. Five samples weighing approximately 2.5 mg were taken fromthe core of the following materials: (i) GUR 1050 UHMWPE barstock thatwas gamma-irradiated to a dose of 10 MRad and subsequently annealed at147° C. (XL-147); and (ii) GUR 1050 UHMWPE barstock that wasgamma-irradiated to a dose of 10 MRad and subsequently annealed at 140°C. (XL-140).

[0148] The samples were crimped into aluminum crucibles and placed inthe DSC chamber. The chamber was continuously flushed with nitrogen gasat a flow rate of approximately 30 ml/min. The reference sample was anempty aluminum crucible. A DSC cycle consisted of a 2 minuteequilibrating at 30° C. followed by heating to 150° C. at 10° C./minrate.

[0149] The temperature corresponding to the peak of the endotherm wastaken as the melting point (T_(m)). The lamellar thickness (l) wascalculated as follows:

l=(2·ψ_(e) ·T _(m) ^(o))/(ΔH·(T _(m) ^(o) −T _(m))·ρ)

[0150] where ψ_(e) is the end free surface energy of polyethylene(2.22×10⁻⁶ cal/cm²), ΔH is the heat of melting of polyethylene crystals(69.2 cal/g), ρ is the density of the crystalline regions (1.0005g/cm³), and T_(m) ^(o) is the melting point of a perfect polyethylenecrystal (418.15 K).

[0151] The mean lamellar thickness values were 369.0 and 346.9Angstroms, respectively, for the XL-147 and XL-140 materials (Table 4,Table 5). TABLE 4 XL-147 (147 degree annealing, 10 MRad XLPE) MeltingTemp lamellar thickness Sample (deg C.) (Angstroms) 1 138.3 398 2 137.4352 3 137.9 376 4 137.7 365 5 137.5 354 avg 137.8 369.0 std dev 0.4 19.1

[0152] TABLE 5 XL-140 (140 degree annealing, 10 MRad XLPE) Melting Templamellar thickness Sample (deg C.) (Angstroms) 1 138.07 385 2 136.68 3213 136.89 329 4 136.72 322 5 137.92 377 137.26 346.9 std dev 0.68 31.5

Example 12 Trans-Vinylene Index

[0153] For polyethylene, the concentration of trans-vinylene units (TVU)has been shown to be linear with adsorbed radiation dose at low doselevels (<40 Mrad) (Lyons et al., 1993). The concentration of TVU cantherefore be used to determine the level of crosslinking in UHMWPE.

[0154] Trans-vinylene concentration was determined for the followingmaterials: (i) GUR 1050 UHMWPE barstock that was gamma-irradiated to adose of 2.5 MRad and subsequently annealed at 150° C. (Gamma2.5); (ii)GUR 1050 UHMWPE barstock that was gamma-irradiated to a dose of 5 MRadand subsequently annealed at 150° C. (Gamma5); (iii) GUR 1050 UHMWPEbarstock that was gamma-irradiated to a dose of 10 MRad and subsequentlyannealed at 147° C. (Gamma10-147); and (iv) GUR 1050 UHMWPE barstockthat was gamma-irradiated to a dose of 10 MRad and subsequently annealedat 140° C. (Gamma10-140). For each material type a rectangular specimen(63.50×12.70×6.35 mm) was machined, and 200 to 250 μm thick samples weresliced using a sledge microtome and a diamond blade. For each slice, IRspectra were obtained using a Bio-Rad FTS 25 spectrometer equipped witha UMA 500 infrared microscope. The square sampling area for eachspectrum was 200 μm2×200 μm². The trans-vinylene index (TVI) wascalculated by normalizing the area under the trans-vinylene vibration at965 cm⁻¹ to that under the 1900 cm⁻¹ vibration. The average TVI for eachmaterial type was taken as the average of four measurements taken atdepths of 0.5, 1.0, 1.5, and 2.0 mm distances from the surface of thespecimens.

[0155] The average TVI values for each material type are shown in FIG.14. The TVI value was found to increase with increasing radiation dose.

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We claim:
 1. A method for isolating wear particles from an ultrahighmolecular weight polyethylene (UHMWPE) medical implant for use in thebody comprising the steps of: crosslinking the UHMWPE; annealing theUHMWPE; machining UHMWPE to form an implant; wear testing the implant;harvesting wear particles; and filtering the particles using 0.05 μm orsmaller pore size filters.
 2. The method of claim 1 wherein saidmachining is performed before said crosslinking.
 3. The method of claim1 wherein said crosslinking is performed using electromagnetic radiationor energetic subatomic particles.
 4. The method of claim 3 wherein saidcrosslinking is performed using gamma radiation.
 5. The method of claim3 wherein said crosslinking is performed using e-beam radiation.
 6. Themethod of claim 3 wherein said crosslinking is performed using x-rayradiation.
 7. The method of claim 1 wherein said crosslinking isperformed using chemical crosslinking.
 8. The method of claim 1 whereinsaid crosslinking is at a dose of greater than five but less than orequal to fifteen MegaRad (MRad).
 9. The method of claim 1 wherein saidcrosslinking is at a dose of greater than five but less than or equal toten MegaRad (MRad).
 10. The method of claim 1 wherein said annealing isperformed in the melt stage.
 11. The method of claim 1 wherein saidannealing is performed in an inert environment.
 12. The method of claim1 wherein said annealing is performed in an ambient environment.
 13. Themethod of claim 1 wherein said wear testing occurs on a joint simulator.14. The method of claim 13 wherein said joint simulator simulates thehip joint of a human.
 15. The method of claim 13 wherein said jointsimulator simulates the knee joint of a human.
 16. The method of claim 1wherein said wear testing occurs in vivo.
 17. The method of claim 1wherein said harvesting is performed using acid digestion.
 18. Themethod of claim 1 wherein said harvesting is performed using basedigestion.
 19. The method of claim 1 wherein said harvesting isperformed using enzymatic digestion.
 20. The method of claim 1 whereinsaid implant has a polymeric structure with greater than about 300angstrom lamellar thickness.
 21. The method of claim 1 wherein saidannealing is performed at or below 150° C.
 22. The method of claim 21wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10.
 23. The method ofclaim 21 wherein the crosslinking is sufficient to form an implant witha trans-vinylene index of greater than about 0.15 and less than about0.20.
 24. The method of claim 1 wherein said annealing is performedbelow about 1 50° C. and above about 140° C.
 25. The method of claim 24wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10.
 26. The method ofclaim 24 wherein the crosslinking is sufficient to form an implant witha trans-vinylene index of greater than about
 0. 15 and less than about0.20.
 27. The method of claim 1 wherein said annealing is performed at147° C.
 28. The method of claim 27 wherein the crosslinking issufficient to form an implant with a trans-vinylene index of greaterthan or equal to 0.10.
 29. The method of claim 27 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than about 0.15 and less than about 0.20.
 30. Themethod of claim 1 wherein said annealing is performed at 140° C.
 31. Themethod of claim 30 wherein the crosslinking is sufficient to form animplant with a trans-vinylene index of greater than or equal to 0.10.32. The method of claim 30 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about 0.15and less than about 0.20.
 33. A method of preparing an UHMWPE medicalimplant for use in the body having a decreased wear particle numbercomprising the steps of: crosslinking the UHMWPE; annealing the UHMWPE;and machining UHMWPE to form an implant; wherein the wear particles thatare decreased in number are greater than 0.125 μm in diameter.
 34. Themethod of claim 33 wherein said machining is performed before saidcrosslinking.
 35. The method of claim 33 wherein said crosslinking isperformed using electromagnetic radiation or energetic subatomicparticles.
 36. The method of claim 35 wherein said crosslinking isperformed using gamma radiation.
 37. The method of claim 35 wherein saidcrosslinking is performed using e-beam radiation.
 38. The method ofclaim 35 wherein said crosslinking is performed using x-ray radiation.39. The method of claim 33 wherein said crosslinking is performed usingchemical crosslinking.
 40. The method of claim 33 wherein saidcrosslinking is at a dose of greater than five but less than or equal tofifteen MegaRad (MRad).
 41. The method of claim 33 wherein saidcrosslinking is at a dose of greater than five but less than or equal toten MegaRad (MRad).
 42. The method of claim 33 wherein said annealing isperformed in the melt stage.
 43. The method of claim 33 wherein saidannealing is performed in an inert environment.
 44. The method of claim33 wherein said annealing is performed in an ambient environment. 45.The method of claim 33 wherein said annealing is performed below orequal to 150° C.
 46. The method of claim 45 wherein the crosslinking issufficient to form an implant with a trans-vinylene index of greaterthan or equal to 0.10.
 47. The method of claim 45 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than about 0.15 and less than or about 0.20.
 48. Themethod of claim 33 wherein said annealing is performed below about 150°C. and above about 140° C.
 49. The method of claim 48 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10.
 50. The method of claim 48wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than about 0.15 and less than about0.20.
 51. The method of claim 33 wherein said annealing is performed at147° C.
 52. The method of claim 51 wherein the crosslinking issufficient to form an implant with a trans-vinylene index of greaterthan or equal to 0.10.
 53. The method of claim 51 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than about 0.15 and less than about 0.20.
 54. Themethod of claim 33 wherein said annealing is performed at 140° C. 55.The method of claim 54 wherein the crosslinking is sufficient to form animplant with a trans-vinylene index of greater than or equal to 0.10.56. The method of claim 54 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about 0.15and less than about 0.20.
 57. The method of claim 33 wherein said weartesting occurs on a joint simulator.
 58. The method of claim 57 whereinsaid joint simulator simulates the hip joint of a human.
 59. The methodof claim 57 wherein said joint simulator simulates the knee joint of ahuman.
 60. The method of claim 33 wherein said wear testing occurs invivo.
 61. The method of claim 33 wherein said harvesting is performedusing acid digestion.
 62. The method of claim 33 wherein said harvestingis performed using base digestion.
 63. The method of claim 33 whereinsaid harvesting is performed using enzymatic digestion.
 64. The methodof claim 33 wherein said implant has a polymeric structure with greaterthan about 300 angstrom lamellar thickness.
 65. A method of decreasingmacrophage response to an UHMWPE medical implant for use in the bodycomprising the steps of: performing wear particle analysis; andcrosslinking the UHMWPE at a dose level exhibiting the lowest particlenumber per million cycles of the hip simulator wherein the number ofparticles present was determined using a 0.05 μm or smaller pore sizefilter.
 66. A method of decreasing macrophage response to an UHMWPEmedical implant for use in the body comprising crosslinking UHMWPE priorto implantation in a patient wherein the total volume of wear particlesis decreased and the total number of wear particles is decreased. 67.The method of claim 66 wherein said crosslinking is performed usingelectromagnetic radiation or energetic subatomic particles.
 68. Themethod of claim 67 wherein said crosslinking is performed using gammaradiation.
 69. The method of claim 67 wherein said crosslinking isperformed using e-beam radiation.
 70. The method of claim 67 whereinsaid crosslinking is performed using x-ray radiation.
 71. The method ofclaim 66 wherein said crosslinking is performed using chemicalcrosslinking.
 72. The method of claim 66 wherein said crosslinking is ata dose of greater than five but less than or equal to fifteen MegaRad(MRad).
 73. The method of claim 66 wherein said crosslinking is at adose of greater than five but less than or equal to ten MegaRad (MRad).74. A method of decreasing macrophage response to an UHMWPE medicalimplant for use in the body comprising the steps of: crosslinking theUHMWPE; annealing the UHMWPE; machining UHMWPE to form an implant; weartesting the implant; harvesting wear particles; filtering the particlesusing 0.05 μm pore or smaller size filters; characterizing the wearparticles; determining the number of particulate debris; and selectingthe crosslinking method for implants that gives the lowest number ofparticulate debris.
 75. The method of claim 74 wherein said machining isperformed before said crosslinking.
 76. The method of claim 74 whereinsaid crosslinking is performed using electromagnetic radiation orenergetic subatomic particles.
 77. The method of claim 76 wherein saidcrosslinking is performed using gamma radiation.
 78. The method of claim76 wherein said crosslinking is performed using e-beam radiation. 79.The method of claim 76 wherein said crosslinking is performed usingx-ray radiation.
 80. The method of claim 74 wherein said crosslinking isperformed using chemical crosslinking.
 81. The method of claim 74wherein said crosslinking is at a dose of greater than five but lessthan or equal to fifteen MegaRad (MRad).
 82. The method of claim 74wherein said crosslinking is at a dose of greater than five but lessthan or equal to ten MegaRad (MRad).
 83. The method of claim 74 whereinsaid annealing is performed in the melt stage.
 84. The method of claim74 wherein said annealing is performed in an inert environment.
 85. Themethod of claim 74 wherein said annealing is performed in an ambientenvironment.
 86. The method of claim 74 wherein said annealing isperformed below or equal to 150° C.
 87. The method of claim 86 whereinthe crosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10.
 88. The method of claim 86wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than about 0.15 and less than about0.20.
 89. The method of claim 74 wherein said annealing is performedbelow about 150° C. and above about 140° C.
 90. The method of claim 89wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than or equal to 0.10.
 91. The method ofclaim 89 wherein the crosslinking is sufficient to form an implant witha trans-vinylene index of greater than about 0.15 and less than about0.20.
 92. The method of claim 74 wherein said annealing is performed at147° C.
 93. The method of claim 92 wherein the crosslinking issufficient to form an implant with a trans-vinylene index of greaterthan or equal to 0.10.
 94. The method of claim 92 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than about
 0. 15 and less than about 0.20.
 95. Themethod of claim 74 wherein said annealing is performed at 140° C. 96.The method of claim 95 wherein the crosslinking is sufficient to form animplant with a trans-vinylene index of greater than or equal to 0.10.97. The method of claim 95 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about 0.15and less than about 0.20.
 98. The method of claim 74 wherein said weartesting occurs on ajoint simulator.
 99. The method of claim 98 whereinsaid joint simulator simulates the hip joint of a human.
 100. The methodof claim 98 wherein said joint simulator simulates the knee joint of ahuman.
 101. The method of claim 74 wherein said wear testing occurs invivo.
 102. The method of claim 74 wherein said harvesting is performedusing acid digestion.
 103. The method of claim 74 wherein saidharvesting is performed using base digestion.
 104. The method of claim74 wherein said harvesting is performed using enzymatic digestion. 105.The method of claim 74 wherein said implant has a polymeric structurewith greater than about 300 angstrom lamellar thickness.
 106. The methodof claim 74 wherein the characterization is by a high resolutionmicroscopic method or an automatic particle counter.
 107. The method ofclaim 106 wherein the characterization is by scanning electronmicroscopy.
 108. The method of claim 106 wherein the characterization isby an automatic particle counter.
 109. A method of decreasing macrophageresponse to an UHMWPE medical implant for use in the body comprising thesteps of: crosslinking the UHMWPE; annealing the UHMWPE; machiningUHMWPE to form an implant; wear testing the implant; harvesting wearparticles; filtering the particles using 0.05 μm or smaller pore sizefilters; characterizing the wear particles; determining the number ofparticulate debris; determining the total particle surface area; andselecting the crosslinking method for implants that gives the lowesttotal particle surface area.
 110. The method of claim 109 wherein saidmachining is performed before said crosslinking.
 111. A method ofdecreasing osteolysis of an UHMWPE medical implant for use in the bodycomprising the steps of: crosslinking the UHMWPE; annealing the UHMWPE;machining UHMWPE to form an implant; wear testing the implant;harvesting wear particles; filtering the particles over 0.05 μm orsmaller pore size filters; characterizing the wear particles;determining the number of particulate debris; and selecting thecrosslinking dose level to crosslink implants that exhibits the lowestnumber of particulate debris.
 112. The method of claim 111 wherein saidmachining is performed before said crosslinking.
 113. The method ofclaim 111 wherein said crosslinking is performed using electromagneticradiation or energetic subatomic particles.
 114. The method of claim 113wherein said crosslinking is performed using gamma radiation.
 115. Themethod of claim 113 wherein said crosslinking is performed using e-beamradiation.
 116. The method of claim 113 wherein said crosslinking isperformed using x-ray radiation.
 117. The method of claim 111 whereinsaid crosslinking is performed using chemical crosslinking.
 118. Themethod of claim 111 wherein said crosslinking is at a dose of greaterthan five but less than or equal to fifteen MegaRad (MRad).
 119. Themethod of claim 111 wherein said crosslinking is at a dose of greaterthan five but less than or equal to ten MegaRad (MRad).
 120. The methodof claim 111 wherein said annealing is performed in the melt stage. 121.The method of claim 111 wherein said annealing is performed in an inertenvironment.
 122. The method of claim 111 wherein said annealing isperformed in an ambient environment.
 123. The method of claim 111wherein said annealing is performed below or equal to 150° C.
 124. Themethod of claim 123 wherein the crosslinking is sufficient to form animplant with a trans-vinylene index of greater than or equal to 0.10.125. The method of claim 123 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about 0.15and less than about 0.20.
 126. The method of claim 111 wherein saidannealing is performed below about 150° C. and above about 140° C. 127.The method of claim 126 wherein the crosslinking is sufficient to forman implant with a trans-vinylene index of greater than or equal to 0.10.128. The method of claim 126 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about
 0. 15and less than about 0.20.
 129. The method of claim 111 wherein saidannealing is performed at 147° C.
 130. The method of claim 129 whereinthe crosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10.
 131. The method of claim 129wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than about 0.15 and less than about0.20.
 132. The method of claim 111 wherein said annealing is performedat 140° C.
 133. The method of claim 132 wherein the crosslinking issufficient to form an implant with a trans-vinylene index of greaterthan or equal to 0.10.
 134. The method of claim 132 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than about 0.15 and less than about 0.2.
 135. Themethod of claim 111 wherein said wear testing occurs on a jointsimulator.
 136. The method of claim 135 wherein said joint simulatorsimulates the hip joint of a human.
 137. The method of claim 135 whereinsaid joint simulator simulates the knee joint of a human.
 138. Themethod of claim 111 wherein said wear testing occurs in vivo.
 139. Themethod of claim 1 11 wherein said harvesting is performed using aciddigestion.
 140. The method of claim 111 wherein said harvesting isperformed using base digestion.
 141. The method of claim 111 whereinsaid harvesting is performed using enzymatic digestion.
 142. The methodof claim 111 wherein said implant has a polymeric structure with greaterthan about 300 angstrom lamellar thickness.
 143. The method of claim 111wherein the characterization is by a high resolution microscopic methodor an automatic particle counter.
 144. The method of claim 111 whereinthe characterization is by scanning electron microscopy.
 145. The methodof claim 111 wherein the characterization is by an automatic particlecounter.
 146. A method of decreasing osteolysis of an UHMWPE medicalimplant for use in the body comprising the steps of: crosslinking theUHMWPE; annealing the UHMWPE; machining UHMWPE to form an implant; weartesting the implant; harvesting wear particles; filtering the particlesusing 0.05 μm or smaller pore size filters; characterizing the wearparticles; determining the number of particulate debris; determining thetotal particle surface area; and selecting the crosslinking method forimplants that gives the lowest total particle surface area.
 147. Themethod of claim 146 wherein said machining is performed before saidcrosslinking.
 148. A method of decreasing macrophage response to aUHMWPE medical implant for use in the body comprising the steps ofcrosslinking the UHMWPE, simulating use in a host, and testing serum forparticulate debris using a 0.05 μm pore size filter, wherein particlesof the diameter of 0.1 μm to 1 μm cause increased macrophage response.149. The method of claim 148 wherein said crosslinking is performedusing electromagnetic radiation or energetic subatomic particles. 150.The method of claim 149 wherein said crosslinking is performed usinggamma radiation.
 151. The method of claim 149 wherein said crosslinkingis performed using e-beam radiation.
 152. The method of claim 149wherein said crosslinking is performed using x-ray radiation.
 153. Themethod of claim 148 wherein said crosslinking is performed usingchemical crosslinking.
 154. The method of claim 148 wherein saidcrosslinking is at a dose of greater than five but less than or equal tofifteen MegaRad (MRad).
 155. The method of claim 148 wherein saidcrosslinking is at a dose of greater than five but less than or equal toten MegaRad (MRad).
 156. The method of claim 148 wherein said simulatingoccurs on ajoint simulator.
 157. The method of claim 156 wherein saidsimulating simulates the hip joint of a human.
 158. The method of claim156 wherein said simulating simulates the knee joint of a human.
 159. Acrosslinked UHMWPE medical implant for use in the body that exhibitsdecreased osteolysis (or macrophage response) in comparison toconventional treatment of UHMWPE due to a particle number of less than5×10¹² per year upon testing for wear resistance.
 160. An UHMWPE medicalimplant for use in the body having a decreased wear particle number ofparticles created by the steps comprising of: crosslinking the UHMWPE;annealing the UHMWPE; machining UHMWPE to form an implant; wear testingthe implant; harvesting wear particles; filtering the particles over0.05 μm or smaller pore size filters; characterizing the wear particles;determining the number of particulate debris; and selecting thecrosslinking method to crosslink implants that exhibits the lowestnumber of particulate debris; wherein the wear particles that aredecreased in number are greater than 0.125 μm in diameter.
 161. Theimplant of claim 160 wherein said machining is performed before saidcrosslinking.
 162. The implant of claim 160 wherein said crosslinking isperformed using electromagnetic radiation or energetic subatomicparticles.
 163. The implant of claim 162 wherein said crosslinking isperformed using gamma radiation.
 164. The implant of claim 162 whereinsaid crosslinking is performed using e-beam radiation.
 165. The implantof claim 162 wherein said crosslinking is performed using x-rayradiation.
 166. The implant of claim 160 wherein said crosslinking isperformed using chemical crosslinking.
 167. The implant of claim 160wherein said crosslinking is at a dose of greater than five but lessthan or equal to fifteen MegaRad (MRad).
 168. The implant of claim 160wherein said crosslinking is at a dose of greater than five but lessthan or equal to ten MegaRad (MRad).
 169. The implant of claim 160wherein said annealing is performed in the melt stage.
 170. The implantof claim 160 wherein said annealing is performed in an inertenvironment.
 171. The implant of claim 160 wherein said annealing isperformed in an ambient environment.
 172. The implant of claim 160wherein said annealing is performed below or equal to 150° C.
 173. Theimplant of claim 172 wherein the crosslinking is sufficient to form animplant with a trans-vinylene index of greater than or equal to 0.10.174. The implant of claim 172 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about 0.15and less than about 0.20.
 175. The implant of claim 160 wherein saidannealing is performed below about 150° C. and above about 140° C. 176.The implant of claim 175 wherein the crosslinking is sufficient to forman implant with a trans-vinylene index of greater than or equal to 0.10.177. The implant of claim 175 wherein the crosslinking is sufficient toform an implant with a trans-vinylene index of greater than about 0.15and less than about 0.20.
 178. The implant of claim 160 wherein saidannealing is performed at 147° C.
 179. The implant of claim 178 whereinthe crosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than or equal to 0.10.
 180. The implant of claim 178wherein the crosslinking is sufficient to form an implant with atrans-vinylene index of greater than about
 0. 15 and less than about0.20.
 181. The implant of claim 160 wherein said annealing is performedat 140° C.
 182. The implant of claim 181 wherein the crosslinking issufficient to form an implant with a trans-vinylene index of greaterthan or equal to 0.10.
 183. The implant of claim 181 wherein thecrosslinking is sufficient to form an implant with a trans-vinyleneindex of greater than about 0.15 and less than about 0.20.
 184. Theimplant of claim 160 wherein said wear testing occurs on a jointsimulator.
 185. The implant of claim 184 wherein said joint simulatorsimulates the hip joint of a human.
 186. The implant of claim 184wherein said joint simulator simulates the knee joint of a human. 187.The implant of claim 160 wherein said wear testing occurs in vivo. 188.The implant of claim 160 wherein said harvesting is performed using aciddigestion.
 189. The implant of claim 160 wherein said harvesting isperformed using base digestion.
 190. The implant of claim 160 whereinsaid harvesting is performed using enzymatic digestion.
 191. The implantof claim 160 wherein said harvesting is performed using enzymaticdigestion.
 192. The implant of claim 160 wherein said implant has apolymeric structure with greater than about 300 angstrom lamellarthickness.
 193. The implant of claim 160 wherein the characterization isby a high-resolution microscopic method or an automatic particlecounter.
 194. The implant of claim 160 wherein the characterization isby scanning electron microscopy.
 195. The implant of claim 160 whereinthe characterization is by an automatic particle counter.